DNA damage perturbs genomic stability and has been linked to age-associated cognitive decline, as well as to early stages of various neurodegenerative disorders including Alzheimer?s disease (AD), amyotrophic lateral sclerosis, and frontotemporal dementia (FTD). However, our mechanistic understanding of how DNA damage contributes to neuronal vulnerability and deterioration remains an unresolved, yet extremely important question. A major confounding factor is that the sources of damage that are most pertinent to neurodegeneration remain unknown and the precise mechanisms that connect genomic instability to neurodegeneration are poorly understood. In addition, it is unclear whether the deterioration of brain function results solely from a random accumulation of DNA damage throughout the genome, or whether there are ?hotspots? of damage that mediate this process. The goal of our research is to better understand the mechanisms underlying genomic instability in neurodegeneration and identify novel therapeutic targets to dampen this early pathological hallmark of neuronal vulnerability. We hypothesize that genomic instability is a major underlying mechanism of cognitive decline and neuronal vulnerability in AD and FTD. Towards testing this hypothesis, our specific aims are: 1) to identify genomic loci that are vulnerable to the accumulation of DNA damage, particularly DNA double strand breaks (DSBs) in mouse and human induced pluripotent cell (iPSC)-derived models of AD and FTD, 2) to determine the precise defects in DSB signaling/repair in mouse and human iPSC-derived models of AD and FTD, and 3) to identify modifiers that reduce DNA damage susceptibility in iPSC-derived neural cells from patients with familial AD and FTD using a novel high-throughput screening strategy. Our preliminary findings suggest that excessive DNA DSBs are an early pathological hallmark of neurodegeneration that can be modeled in both mouse and human systems. Obtaining increased mechanistic insight into the failure to respond to and/or repair DNA DSBs in the context of neurodegenerative mutations will broaden our understanding of how genomic instability contributes to decline in brain health and cognition, and provide novel avenues for early therapeutic intervention in neurodegeneration.